Depression is a common, frequently-occurring disease which poses a threat to human health. It is characterized by depressive emotions and falls into the psychiatric category of affective disorders. The signs of depression include low mood, slow thinking and distress. The principal disturbances are feelings of sadness, despair, worthlessness and helplessness, and a loss of interest or pleasure in daily activities. Psychologically, it may be accompanied by anxiety, feelings of guilt, delusion and hallucinations, decreased concentration and memory as well as suicide attempts. The physical signs are sleep disturbance, appetite loss, weight loss, sexual hypoactivity, restlessness and fatigue.
The development of depression is slow, generally, lasting for weeks or months. Some patients whose illness is induced by psychological and social factors may have acute symptoms. In the initial phase, patients usually suffer from insomnia, poor appetite, lethargy and decreased working efficiency. Later, symptoms include distress and despair, even thoughts of suicide may gradually occur.
It is reported that during their lifetime, 6-8% of people in western developed countries suffer from depression which is a common psychiatric disease. As the population has aged, the incidence has increased to 20-50% among people over the age of 60. Statistics indicate that the incidence of depression in the U.S. is second only to that of heart disease and has an annual cost of $44 billion. Depression is fast becoming a serious global problem as well.
In China, due to the acceleration of the pace of life and the increasing intensity of various pressures, the incidence of mental illness has been rising annually. The diagnosis of depression and therapies for treating it are attracting the attention of communities and primary clinical institutions as well as patients. Currently, patients with depression account for 20-30% of the total population of psychiatric wards. It is estimated by experts that the proportion of depression patients treated in China will increase from 25% at present to 40% in 2010. More women experience depression than men probably due to a heavier burden from daily life and a longer exposure to unpredictable stressors. The incidences of depression are high among the population but the causes of depression are not clear. It may involve a combination of social, psychological, genetic, and biochemical imbalances as well as neuroendocrine changes. The present domestic market scale for antidepressants in China is very small, but grows very fast. Hence, the market for antidepressants has great potential for developers of new drugs.
Currently, depression is mainly treated by administration of antidepressants. In the 1950s, the first drug developed for the treatment of depression was monoamine oxidase inhibitor (MAOI). Due to the severity of its adverse effects, it was replaced by tricyclic antidepressants (TCAs). Selective serotonin re-uptake inhibitors (SSRIs) are at present the chiefly-prescribed drugs. Compared with the first generation of antidepressants, the second generation drugs are safer and better tolerated. Although TCAs such as imipramine, amitriptyline, doxepin, chlorimipramine, desipramine and protriptyline are effective and curative, they are less safe. And overdosing causes higher mortality. These drugs often cause such side effects as symptoms of cardiovascular toxicity, over-mitigation and high levels of anti-cholinergics. Moreover, they act with slow efficacy and multiple doses must be taken daily for a long period, so patients do not become overly reliant on them. Patients administered SSRIs show better tolerance and fewer side effects, especially less cardiovascular toxicity and lower anti-cholinergic concentration, but can develop stomach and intestinal problems as well as sexual disturbances. Higher occurrence of over-mitigation, dry mouth and constipation is observed when paroxetine is used. Higher occurrence of anxiety, restlessness, anorexia and insomnia is observed when fluoxitine is used. Higher occurrence of diarrhea is observed when zoloft is used. Currently, there is no ideal antidepressant that has only minor side effects, even when used in combination with other medicines, and is safe when used at a stronger than recommended dose.
Moreover, after administration of an SSRI, the most commonly-prescribed drug, many patients suffer from uncomfortable stomach and intestinal problems. Sleep and sexual disturbances are more prevalent than with administration of TCAs. The “5-HT syndrome” has drawn particular interest. This syndrome is induced by over-stimulation of the receptor 5-HT1A in the brain stem, and the clinical signs include myoclonus, hyperpyrexia, high blood pressure and even death. It is reported that patients have a greater tendency to commit suicide after administration of certain antidepressants. Therefore, the development of a natural antidepressant with better safety and efficacy is of the highest priority.
Protopanaxadiols are aglycone of panaxadiol saponins. They consist of 20(S)-protopanaxadiol and 20(R)-protopanaxadiol which constitute an enantiomer pair. Their structures are shown below:

20(S)-protopanaxadiol is a principal aglycone of panaxadiol saponins. Chinese patent applications Nos. 02146549.5 and 200410002109.5 report its anti-tumor activity, but there is no prior report with its anti-depression activity.